Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine.

The chromosomal high mobility group box-1 (HMGB1) protein acts as a proinflammatory cytokine when released in the extracellular environment by necrotic and inflammatory cells. In the present study, we show that HMGB1 exerts proangiogenic effects by inducing MAPK ERK1/2 activation, cell proliferation, and chemotaxis in endothelial cells of different origin. Accordingly, HMGB1 stimulates membrane ruffling and repair of a mechanically wounded endothelial cell monolayer and causes endothelial cell sprouting in a three-dimensional fibrin gel. In keeping with its in vitro properties, HMGB1 stimulates neovascularization when applied in vivo on the top of the chicken embryo chorioallantoic membrane whose blood vessels express the HMGB1 receptor for advanced glycation end products (RAGE). Accordingly, RAGE blockade by neutralizing Abs inhibits HMGB1-induced neovascularization in vivo and endothelial cell proliferation and membrane ruffling in vitro. Taken together, the data identify HMGB1/RAGE interaction as a potent proangiogenic stimulus

Cognitive reserve index and functional and cognitive outcomes in severe acquired brain injury: A pilot study

Background: Many variables affect outcome after brain injury. Cognitive reserve (CR) is a subjective factor that reflects a set of personal characteristics and that differentiates individuals. It may influence an individual’s capacity to react to brain injury. Objective: To study the effects of cognitive reserve on functional and cognitive outcome at the end of rehabilitation, in patients with severe acquired brain injury (sABI), by means of the Cognitive Reserve Index questionnaire (CRIq). Methods: We report a retrospective study of a continuous series of sABI patients on first admission to a rehabilitation center. Disability and cognitive outcomes were recorded. Results: In the 94 patients enrolled, the assessments after rehabilitation showed a significant gain measured with the disability Rating Scale for patients with a higher CR (CRIq≥ 85). A significant negative correlation was found: between CRIq scores and the interval elapsing before first access to neuropsychological assessment, between CRIq scores, especially level of education, and tests that measure the same domain (attention). Conclusions: Improvements in overall and cognitive disability emerged, but CR did not seem to substantially influence outcome in this sample of patients. This result may be partly due to the clinical severity of the population studied and the sample’s dimension, although quantitatively representative of the population

Studying monogenetic volcanoes with a Terrestrial Laser Scanner: Case study at Croscat volcano (Garrotxa Volcanic Field, Spain)

Erosional processes (natural or anthropogenic) may partly destroy the relatively small-sized volcanic edifices characteristic of monogenetic volcanic zones, leaving their internal structure well exposed. Nevertheless, the study of these outcrops may be extremely challenging due to restricted accessibility or safety issues. Digital representations of the outcrop surface have been lately used to overcome such difficulties. Data acquired with terrestrial laser scanning instruments using Light Detection and Ranging technology enables the construction of such digital outcrops. The obtained high-precision 3-D terrain models are of greater coverage and accuracy than conventional methods and, when taken at different times, allow description of geological processes in time and space. Despite its intrinsic advantages and the proven satisfactory results, this technique has been little applied in volcanology-related studies. Here, we want to introduce it to the volcanological community together with a new and user-friendly digital outcrop analysis methodology for inexperienced users. This tool may be useful, not only for volcano monitoring purposes, but also to describe the internal structure of exposed volcanic edifices or to estimate outcrop erosion rates that may be helpful in terms of hazard assessment or preservation of volcanic landscapes. We apply it to the Croscat volcano, a monogenetic cone in the La Garrotxa Volcanic Field (Catalan Volcanic Zone, NE Spain), quarrying of which leads to a perfect view of its interior but restricts access to its uppermost parts. Croscat is additionally one of the most emblematic symbols of the La Garrotxa Volcanic Field Natural Park, and its preservation is a main target of the park administration

Heterodimer of A2A and Oxytocin Receptors Regulating Glutamate Release in Adult Striatal Astrocytes

Background: Roles of astrocytes in the modulatory effects of oxytocin (OT) in central nervous system are increasingly considered. Nevertheless, OT effects on gliotransmitter release have been neglected. Methods: In purified astrocyte processes from adult rat striatum, we assessed OT receptor (OTR) and adenosine A2A receptor expression by confocal analysis. The effects of receptors activation on glutamate release from the processes were evaluated; A2A-OTR heteromerization was assessed by co-immunoprecipitation and PLA. Structure of the possible heterodimer of A2A and OT receptors was estimated by a bioinformatic approach. Results: Both A2A and OT receptors were expressed on the same astrocyte processes. Evidence for A2A-OTR receptor-receptor interaction was obtained by measuring the release of glutamate: OT inhibited the evoked glutamate release, while activation of A2A receptors, per se ineffective, abolished the OT effect. Biochemical and bio-physical evidence for A2A-OTR heterodimers on striatal astrocytes was also obtained. The residues in the transmembrane domains 4 and 5 of both receptors are predicted to be mainly involved in the heteromerization. Conclusions: When considering effects of OT in striatum, modulation of glutamate release from the astrocyte processes and of glutamatergic synapse functioning, and the interaction with A2A receptors on the astrocyte processes should be taken into consideration

The Bloom's syndrome helicase (BLM) interacts physically and functionally with p12, the smallest subunit of human DNA polymerase δ

Bloom's syndrome (BS) is a cancer predisposition disorder caused by mutation of the BLM gene, encoding a member of the RecQ helicase family. Although the phenotype of BS cells is suggestive of a role for BLM in repair of stalled or damaged replication forks, thus far there has been no direct evidence that BLM associates with any of the three human replicative DNA polymerases. Here, we show that BLM interacts specifically in vitro and in vivo with p12, the smallest subunit of human POL δ (hPOL δ). The hPOL δ enzyme, as well as the isolated p12 subunit, stimulates the DNA helicase activity of BLM. Conversely, BLM stimulates hPOL δ strand displacement activity. Our results provide the first functional link between BLM and the replicative machinery in human cells, and suggest that BLM might be recruited to sites of disrupted replication through an interaction with hPOL δ. Finally, our data also define a novel role for the poorly characterized p12 subunit of hPOL δ

Synchronous and metachronous colorectal liver metastases: Impact of primary tumor location on patterns of recurrence and survival after hepatic resection

Background: Considerable differences in terms of prognosis exist between the right-sided (RCC) and the left-sided colon cancer (LCC). Aim of the work: In this study, we evaluated prognostic implications of primary tumor location (PTL) among patients who underwent curative-intent hepatectomy for synchronous (SM) and metachronous (MM) colorectal liver metastases (CRLM). Methods: The study population included all consecutive patients affected by CRLM scheduled for first liver resection at three Italian oncological centers. Results: A total of 204 patients who underwent CRLM resection were included, 50% with RCC. Synchronous lesions were prevalent (n=133, 65%). Median OS was respectively 40.3 months for SM-RCC, 53.5 months for SM-LCC, 64.5 months for MM-RCC and 81.6 months for MM-LCC. Patients with MM-LCC showed an OS better than patients with SM-RCC (p=0.008) and SM-LCC (p=0.002). PTL had no influence on RFS. RCC group had less recurrences (75% vs 86.5%), though further surgery with curative-intent was possible more in LCC group (29.3% vs 32.5%). Cox proportional hazards model analysis showed that age and the presence of SM vs MM was associated with a significantly higher hazard ratio (HR) for death (HR=1.024; 95%CI=1.005-1.043; p=0.011 and HR=2.010; 95%CI=1.328-3.043; p=0.001, respectively). Conclusions: We confirmed that patients with CRLM and right-sided primary colon cancer experience worse survival after hepatic resection. The timing of metastasis has been revealed as important prognostic factor

Optimizing PD-L1 evaluation on cytological samples from advanced non-small-cell lung cancer

Aim: Programmed cell death-ligand 1 (PD-L1) predicts response to immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) patients. Most NSCLCs are diagnosed at an advanced stage and using minimally invasive diagnostic procedures that yield small biopsies or cytological samples. Methods: Cytological smears and paired histological samples from 52 advanced NSCLC patients were tested for PD-L1 expression by immunocyto/histochemistry (ICC/IHC) and for PD-L1 gene status by FISH. Results: PD-L1 was overexpressed in 9/52 (17%) cytological samples and in seven (13.5%) matched biopsies. The concordance between immunocytochemistry and IHC was 92.3% (48/52; p < 0.001). The concordance between PD-L1 gene status on cytology and histology was 69.2% (18/26; p < 0.001). No correlation between IHC and fluorescence in situ hybridization results was found. Conclusion: Our data support the feasibility and reliability of PD-L1 protein and PD-L1 gene assessment on direct cytological smears from NSCLC patients whenever histological sample are inadequate

Análisis de las tasas municipales en la Provincia de Buenos Aires

El estudio realiza un análisis de los recursos propios de las municipalidades de la Provincia de Buenos Aires (PBA). A tal efecto se incluye: • Un marco conceptual del financiamiento de los gobiernos municipales. • Un relevamiento de todos los tributos utilizados a nivel municipal, en cumplimiento de los establecido por el Acuerdo Fiscal de 2017. • Una cuantificación de las relaciones básicas del financiamiento municipal.Facultad de Ciencias Económica

High levels of Notch intracellular cleaved domain are associated with stemness and reduced bevacizumab efficacy in patients with advanced colon cancer

δ-like ligand 4 (DLL4)-Notch signaling is associated with tumor resistance to anti-vascular endothelial growth factor (VEGF) therapy. Furthermore, Notch signaling is critical for the maintenance of colon cancer stem cells (CSCs), which are relevant in drug resistance and tumor angiogenesis. CD44 is a transmembrane glycoprotein and is considered a putative marker of CSCs. To assess the association of Notch intracellular cleaved domain (NICD), DLL4 and CD44 expression with the efficacy of anti‑angiogenic drugs, a series of samples derived from patients with advanced colon cancer enrolled in prospective clinical trials were analyzed. Histological samples from 51 primary tumors that originated from patients treated with bevacizumab‑based first‑line chemotherapy were analyzed by immunohistochemistry for NICD, DLL4 and CD44 expression, and CD31 for microvessel count. The expression levels of genes relevant for angiogenesis [angiopoietin (ANGPT)1, ANGPT2, fibroblast growth factor (FGF)1, FGF2, epidermal growth factor, placental growth factor, VEGFA and DLL4] were detected by reverse transcription-quantitative PCR using RNA extracte

PTEN status in advanced colorectal cancer treated with cetuximab

BACKGROUND: Loss of phosphatase and tensin homologue deleted in chromosome 10 (PTEN) function in advanced colorectal cancer (CRC) may represent one of the resistance mechanisms to cetuximab by interfering with the epidermal growth factor receptor signal transduction pathway. METHODS: PTEN expression tested by indirect immunofluorescence was evaluated both on primary (n¼43) and on metastatic (n¼24) sites in CRC patients treated with cetuximab. RESULTS: The loss of PTEN expression tested on metastatic sites was negatively associated with response (100% progressive disease (PD) in PTEN-negative cases vs 30% PD in PTEN-positive cases; Po0.05), PFS (0.8 vs 8.2 months; Po0.001) and OS (2.9 vs 14.2 months; Po0.001). CONCLUSION: A potential role of PTEN in the anti-tumour activity of cetuximab could be hypothesised